NM_177402.5:c.923C>T

Variant names:

• chr1-202599348-G-A
• rs587777782
• NM_177402.5:c.923C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_177402.5(SYT2):​c.923C>T​(p.Pro308Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P308P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT2 NM_177402.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.90

Genes affected

SYT2 (HGNC:11510): (synaptotagmin 2) This gene encodes a synaptic vesicle membrane protein. The encoded protein is thought to function as a calcium sensor in vesicular trafficking and exocytosis. Mutations in this gene are associated with myasthenic syndrome, presynaptic, congenital, with or without motor neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_177402.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-202599348-G-A is Pathogenic according to our data. Variant chr1-202599348-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156369.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT2	NM_177402.5	c.923C>T	p.Pro308Leu	missense_variant	Exon 8 of 9	ENST00000367268.5	NP_796376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYT2	ENST00000367268.5	c.923C>T	p.Pro308Leu	missense_variant	Exon 8 of 9	1	NM_177402.5	ENSP00000356237.4
SYT2	ENST00000367267.5	c.923C>T	p.Pro308Leu	missense_variant	Exon 8 of 9	2		ENSP00000356236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 7 Pathogenic:4

Feb 04, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SYT2 c.923C>T variant is classified as Likely Pathogenic (PS4_supporting, PM2, PP1_strong, PP3) The SYT2 c.923C>T variant is a single nucleotide change in exon 8/9 of the SYT2 gene, which is predicted to change the amino acid proline at position 308 in the protein to leucine. This variant has been reported to co-segregate with disease in a UK family with several affected individuals over four generations. This family presented with childhood-onset foot deformities, lower limb weakness and wasting with areflexia. In some cases additional fatigability of the eye and limb muscles was observed (PMID:26519543, PMID:26519543) (PS4_supporting, PP1-strong). This variant is in dbSNP (rs587777782), but is absent from population databases (PM2). This variant has been reported in ClinVar as pathogenic for Myasthenic syndrome, congenital, presynaptic by another diagnostic laboratory (ClinVar Variation ID: 156369) and also as damaging for nonprogressive motor neuropathy in the disease database HGMD (CM149796). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 17, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Moderate, PS4_Supporting, PM2, PP1, PP3 -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 308 of the SYT2 protein (p.Pro308Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital myasthenic syndrome (PMID: 25192047). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156369). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SYT2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SYT2 function (PMID: 28953919). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Uncertain:1

Jun 11, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.84		Gain of MoRF binding (P = 0.0602);Gain of MoRF binding (P = 0.0602);
MVP		0.79
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777782; hg19: chr1-202568476;